Polyamino acid-catalyzed process for the enantioselective epoxidation of alpha, beta-unsaturated enones and alpha, beta-unsaturated sulfones

ABSTRACT

The invention relates to a novel process that makes it possible to epoxidize α,β-unsaturated enones or α,β-unsaturated sulfones with high conversions and enantiomeric excesses in a two-phase system without addition of water in the presence of an organic solvent, a base, an oxidant, a diastereomer- and enantiomer-enriched homo-polyamino acid that has not been separately preactivated as catalyst, and a specific phase-transfer catalyst as cocatalyst.

BACKGROUND OF THE INVENTION

[0001] The invention relates to a novel polyamino acid-catalyzed processfor the enantioselective epoxidation of α,β-unsaturated enones andα,β-unsaturated sulfones under two-phase conditions in the presence ofspecific cocatalysts.

[0002] Chiral, nonracemic epoxides are known as valuable synthons forpreparing optically active drugs and materials (for example (a) Bioorg.Med. Chem., 1999, 7, 2145-2156; and (b) Tetrahedron Lett., 1999, 40,5421-5424). These epoxides can be prepared by enantioselectiveepoxidation of double bonds. In this case, two stereocenters areproduced in one synthetic step. It is therefore not surprising that alarge number of methods have been developed for the enantioselectiveepoxidation of double bonds. However, there is still a great need fornovel, improved methods for enantioselective epoxidation.

[0003] The epoxidation methods limited to the specific substrates ineach case include methods for the enantioselective epoxidation ofα,β-unsaturated enones.

[0004] Thus, for example, the use of chiral, nonracemic alkaloid-basedphase-transfer catalysts for the epoxidation of enones is described inTetrahedron Lett., 1998, 39, 7563-7566, Tetrahedron Lett., 1998, 39,1599-1602, and Tetrahedron Lett., 1976, 21, 1831-1834.

[0005]Tetrahedron Lett., 1998, 39, 7353-7356, Tetrahedron Lett., 1998,39, 7321-7322, and Angew. Chem., Int. Ed. Enql., 1997, 36, 410-412furthermore describe possibilities for the metal-catalyzed asymmetricepoxidation of enones using organic hydroperoxides.

[0006] WO-A 99/52886 further describes the possibility ofenantioselective epoxidation of enones in the presence of catalystsbased on sugars. Another method for epoxidation using Zn organyls andoxygen in the presence of an ephedrine derivative has been published inLiebigs Ann./Recueil, 1997, 1101-1113.

[0007]Angew. Chem., Int. Ed. Enql., 1980, 19, 929-930, Tetrahedron,1984, 40, 5207-5211, and J. Chem. Soc., Perkin Trans. 1, 1982, 1317-24describe what is known as the classical three-phase Juliá epoxidationmethod. In this method, the enantioselective epoxidation ofα,β-unsaturated enones is carried out with the addition of enantiomer-and diastereomer-enriched polyamino acids in the presence of aqueoushydrogen peroxide and NaOH solution and of an aromatic or halogenatedhydrocarbon as solvent. Further developments of these so-calledthree-phase conditions are to be found in Org. Synth.; Mod. Trends,Proc. IUPAC Symp. 6th., 1986, 275. The method is now generally referredto as the Juliá-Colonna epoxidation.

[0008] According to EP-A 403,252, it is possible also to employaliphatic hydrocarbons advantageously in this Juliá-Colonna epoxidationin place of the original solvents.

[0009] According to WO-A 96/33183 it is furthermore possible in thepresence of the phase-transfer catalyst Aliquat® 336([(CH₃)(C₈H₁₇)₃N⁺]Cl⁻) and using at the same time sodium perborate,which is of low solubility in water, instead of hydrogen peroxide, forthe required amount of base (NaOH) to be reduced, compared with theoriginal conditions of Juliá and Colonna (Tetrahedron, 1984, 40,5207-5211), from about 3.7 to 1 equivalent.

[0010] Despite these improvements, the three-phase conditions havedistinct disadvantages. The reaction times under the original conditionsare in the region of days even for reactive substrates. For example, 1-6days are required for trans-chalcone, depending on the polyamino acidused (Tetrahedron, 1984, 40 5207-5211). A preactivation of the polyaminoacid carried out in the reaction vessel, by stirring in the solvent withthe addition of NaOH solution for 12 to 48 hours, shortens the reactiontime for many substrates to 1 to 3 days. In this case, no intermediateworkup of the catalyst is necessary (EP-A 403,252). The preactivationcan be reduced to a minimum of 6 h in the presence of the NaOH/hydrogenperoxide system (J. Chem. Soc., Perkin Trans. 1, 1995, 1467-1468).

[0011] Despite this improvement, the three-phase method cannot beapplied to substrates which are sensitive to hydroxide ions (J. Chem.Soc., Perkin Trans. 1, 1997, 3501-3507). A further disadvantage of theseclassical conditions is that the polyamino acid forms a gel during thereaction (or even during the preactivation). This restricts the requiredmixing during the reaction and impedes the working up of the reactionmixture.

[0012]Tetrahedron Lett., 2001, 42, 3741-43 discloses that under thethree-phase conditions the addition of the phase-transfer catalyst (PTC)Aliquat 336 in the epoxidation of phenyl-E-styryl sulfone leads to onlya slow reaction rate (reaction time: 4 days) and a poor enantiomericexcess (21% ee). To date, no example of the use of PTCs for theepoxidation of α,β-unsaturated enones under the classical three-phaseJuliá-Colonna conditions has been disclosed.

[0013] The Juliá-Colonna epoxidation has been improved further by achange in the reaction procedure. According to Chem. Commun., 1997,739-740, (pseudo)-anhydrous reaction conditions can be implemented byusing THF, 1,2 dimethoxyethane, tert-butyl methyl ether, or ethylacetate as solvent, a non-nucleophilic base (for example, DBU), and aurea/hydrogen peroxide complex as oxidant. The epoxidation takes placedistinctly more quickly under these so-called two-phase reactionconditions. According to J. Chem. Soc., Perkin Trans. 1, 1997,3501-3507, therefore, the enantioselective epoxidation ofhydroxide-sensitive enones under the Juliá-Colonna conditions is alsopossible for the first time in this way.

[0014] However, the observation that, on use of the two-phaseconditions, the polyamino acid must be preactivated in a separateprocess in order to achieve rapid reaction times and high enantiomericexcesses proves to be a distinct disadvantage. Several days are neededfor this preactivation, which takes place by stirring the polyamino acidin a toluene/NaOH solution. According to Tetrahedron Lett., 1998, 39,9297-9300, the required preactivated catalyst is then obtained after awashing and drying procedure. However, the polyamino acid activated inthis way forms a paste under the two-phase conditions, which impedesmixing during the reaction and the subsequent workup. According to EP-A1,006,127, this problem can be solved by adsorbing the activatedpolyamino acid onto a solid support. Polyamino acids supported on silicagel are referred to as SCAT (silica adsorbed catalysts).

[0015] According to EP-A 1,006,111, a further variant of theJuliá-Colonna epoxidation is catalysis of the enantioselectiveepoxidation by the activated polyamino acid in the presence of water, awater-miscible solvent (for example, 1,2-dimethoxyethane), and sodiumpercarbonate. However, the use of water-miscible solvents complicatesthe workup (extraction) in this process.

[0016] In the Juliá-Colonna epoxidation, the reaction rate and theenantiomeric excess (ee) that can be achieved depend greatly on thepolyamino acid used and the mode of preparation thereof (Chirality,1997, 9, 198-202). In order to obtain approximately comparable results,a standard system with poly-L-leucine (pll) as catalyst andtrans-chalcone as precursor is used throughout for the development anddescription of novel methods in the literature. However, besides D- orL-polyleucine, other polyamino acids such as, for example D- orL-neopentylglycine are also used successfully (EP-A 1,006,127).

[0017] The object of the present invention was to provide a process thatmakes the homo-polyamino acid-catalyzed enantioselective epoxidation ofα,β-unsaturated enones and α,β-unsaturated sulfones possible but is notsubject to the disadvantages of the above-described variants of theJuliá-Colonna epoxidation. It was intended in particular to find a rapidand broadly applicable method that avoids the separate, time-consumingand complicated preactivation of the polyamino acid. At the same time,it was intended that the process have advantages in relation to thespace/time yield, handling, economics, and ecology on the industrialscale.

[0018] It has now been found, surprisingly, that the epoxidation ofα,β-unsaturated enones and α,β-unsaturated sulfones can be carried outunder two-phase conditions in the presence of a polyamino acid, ascatalyst, that has not been subjected to previous separate activationwhen the epoxidation takes place in the presence of a phase-transfercatalyst. This procedure surprisingly makes it possible for the reactiontimes to be very short with, at the same time, high enantiomericexcesses.

SUMMARY OF THE INVENTION

[0019] The invention thus relates to a process for the epoxidation ofα,β-unsaturated enones or α,β-unsaturated sulfones in the presence of

[0020] (1) an organic solvent,

[0021] (2) a base,

[0022] (3) an oxidant,

[0023] (4) a diastereomer- and enantiomer-enriched homo-polyamino acidas catalyst that has not been separately preactivated, and

[0024] (5) a phase-transfer catalyst,

[0025] but without addition of water.

DETAILED DESCRIPTION OF THE INVENTION

[0026] It is crucial that the process according to the invention becarried out in the presence of a phase-transfer catalyst. Examples thatcan be used are quaternary ammonium salts, quaternary phosphonium salts,onium compounds, or pyridinium salts.

[0027] Phase-transfer catalysts that have proved particularly suitableare quaternary ammonium or phosphonium salts of the general formula (I)

(R¹R²R³R⁴A)⁺X⁻  (I)

[0028] in which

[0029] A is N or P,

[0030] X⁻ is an inorganic or organic anion,

[0031] R¹ and R² are identical or different and are alkyl, aryl,aralkyl, cycloalkyl, or heteroaryl radicals that are optionallysubstituted by one or more identical or different halogen radicals, and

[0032] R³ and R⁴ are identical or different and are alkyl, aryl,aralkyl, cycloalkyl, or heteroaryl radicals that are optionallysubstituted by one or more identical or different halogen radicals, orR³ and R⁴ together form a C₄-C₆-cycloalkyl ring with A.

[0033] Phase-transfer catalysts of the general formula (I) that haveproved suitable are those in which A and X⁻ have the above-mentionedmeanings, and R¹, R², R³, and R⁴ are identical or different and areC₁-C₁₈-alkyl, C₆-C₁₈-aryl, C₇-C₁₉-aralkyl, C₅-C₇-cycloalkyl, orC₃-C₁₈-heteroaryl.

[0034] Particularly suitable phase-transfer catalysts are((C₄H₉)₄N)⁺Hal⁻ (particularly ((C₄H₉)₄N)⁺Br⁻),((C₄H₉)₄P)⁺Hal⁻(particularly ((C₄H₉)₄P)³⁰ Br⁻), ((C₄H₉)₄N)⁺HSO₄ ⁻,((C₈H₁₇)₄N)⁺Br⁻, [(CH₃)(C₈H₁₇)₃N⁺]Cl⁻, and [(CH₃)(C₄H₉)₃N⁺]Cl⁻.

[0035] X⁻ in the general formula (I) is an inorganic or organic cation,preferably F⁻, Cl⁻, Br⁻, I⁻, OH⁻, HSO₄ ⁻, SO₄ ⁻, NO₃ ⁻, CH₃COO⁻,CF₃COO⁻, C₂H₅COO⁻, C₃H₇COO⁻, CF₃SO₃ ⁻, or C₄F₉SO₃ ⁻.

[0036] The phase-transfer catalysts to be employed according to theinvention are normally commercially available or else can be prepared bymethods familiar to the skilled person.

[0037] The amount of added phase-transfer catalyst is not critical andis normally in the range 0.1 to 20 mol % (preferably in the range 0.5 to15 mol %, particularly preferably in the range 0.5 to 11 mol %), in eachcase based on the α,β-unsaturated enones or α,β-unsaturated sulfoneemployed. However, it is to be observed with amounts that are even lowerthan 0.1 mol % that the reaction rate decreases markedly, while the highenantiomeric excess is unchanged.

[0038] It is possible to employ as α,β-unsaturated enones orα,β-unsaturated sulfones the compounds of the general formula (II)

[0039] in which

[0040] X is (C═O) or (SO₂), and

[0041] R⁵ and R⁶ are identical or different and are (C₁-C₁₈)-alkyl,(C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl,(C₇-C₁₉)-aralkyl, (C₁-C₁₈)-heteroaryl or (C₂-C₁₉)-heteroaralkyl, each ofwhich radicals is optionally substituted once or more than once byidentical or different radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸,SO₀₋₃R⁷, OR⁷, CO₂R⁷, CONHR⁷, or COR⁷, and where optionally one or moreCH₂ groups in the radicals R⁵ and R⁶ are replaced by O, SO₀₋₂, NR⁷, orPO₀₋₂R⁷,

[0042] where R⁷ and R⁸ are identical or different and are H,(C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl,(C₆-C₁₈)-aryl, (C₁-C₁₈)-heteroaryl, (C₁-C₈)-alkyl-(C₆-C₈)-aryl,(C₁-C₈)-alkyl-(C₁-C₁₉)-heteroaryl, or (C₁-C₈)-alkyl-(C₃-C₈)-cycloalkyl,each of which radicals R⁷ and R⁸ is optionally substituted once or morethan once by identical or different halogen radicals.

[0043] A (C₁-C₁₈)-alkyl radical means for the purpose of the invention aradical that has 1 to 18 saturated carbon atoms and that may havebranches anywhere. It is possible to include in this group in particularthe radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, and hexyl.

[0044] A (C₂-C₁₈)-alkenyl radical has the features mentioned for the(C₁-C₁₈)-alkyl radical, with the necessity for at least onecarbon-carbon double bond to be present within the radical.

[0045] A (C₂-C₁₈)-alkynyl radical has the features mentioned for the(C₁-C₁₈)-alkyl radical, with the necessity for at least onecarbon-carbon triple bond to be present within the radical.

[0046] A (C₃-C₈)-cycloalkyl radical means a cyclic alkyl radical having3 to 8 carbon atoms and, where appropriate, a branch anywhere. Includedare, particularly, radicals such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. One or more double bonds maybe present in this radical.

[0047] A (C₆-C₁₈)-aryl radical means an aromatic radical having 6 to 18carbon atoms. Included are, particularly, radicals such as phenyl,naphthyl, anthryl, and phenanthryl.

[0048] A (C₇-C₁₉)-aralkyl radical means a (C₆-C₁₈)-aryl radical linkedvia a (C₁-C₈)-alkyl radical to the molecule.

[0049] A (C₁-C₁₈)-heteroaryl radical designates for the purpose of theinvention a five-, six-, or seven-membered aromatic ring system that has1 to 18 carbon atoms and that has one or more heteroatoms (preferably N,O, or S) in the ring. These heteroaryl radicals include, for example, 2-or 3-furyl, 1-, 2-, and 3-pyrrolyl, 2- and 3-thienyl, 2-, 3-, and4-pyridyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, and 5-pyrazolyl,2-, 4-, and 5-imidazolyl, 1-, 3-, 4-, and 5-triazolyl, 1-, 4-, and5-tetrazolyl, acridinyl, quinolinyl, phen-anthridinyl, 2-, 4-, 5-, and6-pyrimidinyl, and 4-, 5-, 6-, and 7-(1-aza)-indolizinyl.

[0050] A (C₂-C₁₉)-heteroaralkyl radical means a heteroaromatic systemcorresponding to the (C₇-C₁₉)-aralkyl radical.

[0051] Halogen or Hal means in the context of this invention fluorine,chlorine, bromine, and iodine.

[0052] The substrates preferably employed in the process according tothe invention are preferably ax,p-unsaturated enones or α,β-unsaturatedsulfones of the general formula (II) in which R⁵ and R⁶ are identical ordifferent and are (C₁-C₁₂)-alkyl, (C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl,(C₅-C₈)-cycloalkyl, (C₆-C₁₂)-aryl, or (C₁-C₁₂)-heteroaryl, each of whichradicals is optionally substituted once or more than once by identicalor different radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸, or OR⁷, and R⁷and R⁸ have the meanings indicated above for the general formula (II).

[0053] Substrates particularly preferably employed in the processaccording to the invention are α,β-unsaturated enones or α,β-unsaturatedsulfones of the general formula (II) in which R⁵ and R⁶ are identical ordifferent and are (C₁-C₁₂)-alkyl, (C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl,(C₅-C₈)-cycloalkyl, (C₆-C₁₂)-aryl, or (C₁-C₁₂)-heteroaryl, each of whichradicals is optionally substituted once or more than once by identicalor different radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸, or OR⁷, and R⁷and R⁸ have the meanings indicated above for the general formula (II),with the proviso that at least one of the radicals R⁵ or R⁶ is a(C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl, (C₆-C₁₂)-aryl-, or(C₁-C₁₂)-heteroaryl radical.

[0054] It is particularly preferred to subject substrates of the generalformula (III) to the epoxidation according to the invention:

[0055] where

[0056] n and m are identical or different and are the numbers 0, 1, 2 or3,

[0057] R⁹ and R¹⁰ are identical or different and are NR⁷R⁸, NO₂, OR⁷,(C₁-C₁₂)-alkyl, (C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl, (C₅-C₈)-cycloalkyl,(C₆-C₁₂)-aryl, or (C₁-C₁₂)-heteroaryl, each of which radicals R⁹ and R¹⁰is optionally substituted once or more than once by identical ordifferent halogen radicals, and

[0058] R⁷ and R⁸ have the meanings mentioned previously for formula(II).

[0059] A decisive advantage of the process according to the invention isthe fact that homo-polyamino acids that are not preactivated separatelyare employed as catalysts.

[0060] It is possible to use for the process according to the inventiona wide variety of diastereomer- and enantiomer-enriched homo-polyaminoacids. Preference is given, however, to the use of homo-polyamino acidsselected from the group consisting of polyneopentylglycine, polyleucine,polyisoleucine, polyvaline, polyalanine, and polyphenylalanine. The mostpreferred from this group are polyneopentylglycine and polyleucine.

[0061] The chain length of the polyamino acids will be chosen so that,on the one hand, the chiral induction in the reaction is not impairedand, on the other hand, the costs of synthesizing the polyamino acidsare not too great. The chain length of the homo-polyamino acids ispreferably between 5 and 100 (preferably 7 to 50) amino acids. A chainlength of 10 to 40 amino acids is very particularly preferred.

[0062] The homo-polyamino acids can be prepared by state of the artmethods (J. Org. Chem., 1993, 58, 6247 and Chirality, 1997, 9,198-202).The method is to be applied to both optical antipodes of the aminoacids. The use of a particular antipode of a polyamino acid correlateswith the stereochemistry of the epoxide. That is to say, a poly-L-aminoacid leads to the optical antipode of the epoxide that is obtained witha poly-D-amino acid.

[0063] The homo-polyamino acids can be either employed as such unchangedin the epoxidation or previously crosslinked with polyfunctional aminesor chain-extended by other organic polymers. The crosslinking aminesadvantageously employed for a crosslinking are diaminoalkanes(preferably 1,3-diaminopropane) or crosslinked hydroxy- oraminopoly-styrene (CLAMPS, commercially available). Suitable polymerenlargers are preferably nucleophiles based on polyethylene glycol orpolystyrene. Polyamino acids modified in this way are described in Chem.Commun., 1998, 1159-1160, and Tetrahedron: Asymmetry, 1997, 8,3163-3173.

[0064] The amount of the homo-polyamino acid employed is not criticaland is normally in the range 0.0001 to 40 mol % (preferably in the range0.001 to 20 mol %, particularly preferably in the range 0.01 to 15 mol%, and especially in the range 1 to 15 mol %), in each case based on theα,β-unsaturated enone or α,β-unsaturated sulfone employed.

[0065] It is also possible to employ the homo-polyamino acids in a formbound to a support, which may be advantageous in relation to therecoverability of the catalyst and the increase in the optical andchemical yield.

[0066] For this purpose, the homo-polyamino acids are bound byadsorption to an insoluble support material. The insoluble supportmaterials preferably employed are those based on silica or zeolite, suchas, for example, molecular sieves, silica gels, Celite® 521, Celite®Hyflo Super Cell, or Wessalith® DayP. Silica gels with defined poresizes such as, for example, CPC I or CPC II are also advantageous.Further preferred support materials are activated carbon or sugarderivatives such as, for example, nitrocellulose and cellulose.

[0067] The ratio of support material to polyamino acid is given by twolimits. On the one hand, only a certain number of polyamino acids can beadsorbed on the insoluble support, and on the other hand, there is adecline in chiral induction with less than 10% by weight of polyaminoacid relative to the support onwards. The ratio of homo-polyamino acidto support material is preferably in the range from 1:7 to 2:1 parts byweight, particularly preferably in the range from 1:1 to 1:4 parts byweight.

[0068] The method for application to a support is described in detail inEP-A 1,006,127, to which express reference is hereby made. For thispurpose, initially a mixture of the appropriate homo-polyamino acid andthe support material is suspended in an organic solvent such as an ether(for example THF) and then stirred for a prolonged period, preferably upto 48 hours. The solid is then filtered off and dried.

[0069] If such supported catalysts are to be employed, then aparticularly suitable device for the epoxidation process is one capableof retaining only the catalyst. This device is preferably an enzymemembrane reactor (C. Wandrey in Enzymes as Catalysts in OrganicSynthesis; Ed. M. Schneider, Dordrecht Riedel 1986, 263-284). Preferenceis likewise given to a simple fixed bed reactor such as, for example, achromatography column.

[0070] The oxidants usually employed are hydrogen peroxide complexeswith inorganic carbonates, tertiary amines, amino oxides, amides,phosphanes, or phosphane oxides. The urea/hydrogen peroxide complex hasproved particularly suitable.

[0071] The amount of the oxidant employed may be varied within the widelimits of 1 to 10 equivalents. Surprisingly, furthermore, short reactiontimes and high enantiomeric excesses can be achieved even with verysmall amounts of oxidant in the range 1 to 5 equivalents, preferably 1to 3 equivalents, and particularly 1 to 2 equivalents.

[0072] The process according to the invention is carried out in thepresence of a base that may be organic or inorganic. However, organic,non-nucleophilic bases are preferably employed, particularly DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazabicyclo[4.3.0]non-5-ene), or DABCO(1,4-diazabicyclo[2.2.2]octane).

[0073] The amount of the base employed may be varied within the widelimits of 0.1 to 10 equivalents. The reaction according to the inventionstill takes place with short reaction times and high enantiomericexcesses even with amounts of from 0.5 to 5 equivalents, preferably offrom 0.8 to 2 equivalents.

[0074] The process according to the invention is carried out using anorganic solvent Suitable organic solvents are in general ethers(preferably THF, diethyl ether, or tert-butyl methyl ether), esters(preferably ethyl acetate), amides (preferably dimethylformamide), orsulfoxides (preferably dimethyl sulfoxide).

[0075] The temperature used in the epoxidation is generally in the rangefrom −10 to +50° C., preferably in the range from 0 to +40° C., andparticularly at +10 to +30° C.

[0076] In relation to the procedure for the reaction, normally all thecomponents apart from the base are mixed and then the base is added.However, it is also possible to stir the polyamino acid in the presenceof the oxidant, of the base, of the solvent, and of the phase-transfercatalyst for 15 min to 2 hours, and thus preactivate it, and then,without intermediate isolation of the preactivated homo-polyamino acid,to add the substrate to be epoxidized.

[0077] The two-phase process according to the invention for theenantio-selective epoxidation of α,β-unsaturated enones andα,β-unsaturated sulfones is distinguished by the possibility of usinghomo-polyamino acids that have not been preactivated separately. It ispossible with this process, because of the presence of a phase-transfercatalyst, to dispense with the normally necessary time-consuming (3 to 5days) and laborious separate preactivation with intermediate isolation.Substantially higher enantiomeric excesses are usually achieved with theprocess according to the invention.

[0078] The following examples further illustrate details for the processof this invention. The invention, which is set forth in the foregoingdisclosure, is not to be limited either in spirit or scope by theseexamples. Those skilled in the art will readily understand that knownvariations of the conditions of the following procedures can be used.Unless otherwise noted, all temperatures are degrees Celsius and allpercentages are percentages by weight.

EXAMPLES

[0079] The process for preparing polyamino acids often providescatalysts for the Juliá-Colonna epoxidation which vary widely incatalytic activity (Chirality, 1997, 9, 198-202). The conversion perunit time and the enantiomeric excess can be compared for a particularsubstrate only if the same polyamino acid batch is used for theepoxidation reaction. For this reason, direct comparison of new resultswith results published in the literature is impossible, simply becausedifferent catalyst batches are inevitably used. For this reason, auniform polyleucine batch was used in each of the subsequent examplesand comparative examples.

[0080] In all the following examples, the conversion and theenantiomeric excess (ee) were determined by methods known from theliterature using HPLC on a chiral, nonracemic phase (UV detection).

Examples 1 and 3 and Comparative Examples 2 and 4 Epoxidation ofTrans-Chalcone (1) to Epoxychalcone (2) Under Two-Phase and SCATConditions

[0081]

Example 1 2-Phase Conditions with PTC

[0082] 50 mg of trans-chalcone, 35 mg of urea/hydrogen peroxide complex(UHP, 0.36 mmol, 1.5 equivalents), 8.5 mg of [(C₄H₉)₄N⁺]Br⁻, and 100 mgof pll that had not been separately preactivated (11 mol %) were mixedand, after suspending in 1.5 ml of anhydrous THF, 55 μl of DBU (1.5equivalents) were added. The reaction mixture was allowed to react atroom temperature with stirring. After a reaction time of 30 minutes, thereaction mixture was filtered and the filtrate was concentrated underreduced pressure.

Comparative Example CE 2 2-Phase Conditions without PTC

[0083] 50 mg of trans-chalcone, 35 mg of urea/hydrogen peroxide complex(UHP, 0.36 mmol, 1.5 equivalents), and 100 μg of pll that had not beenseparately preactivated (11 mol %) were mixed and, after suspending with1.5 ml of anhydrous THF, 55 μl of DBU (1.5 equivalents) were added. Thereaction mixture was allowed to react with stirring at room temperature.After a reaction time of 30 min, the reaction mixture was filtered andthe filtrate was concentrated under reduced pressure.

Example 3 SCAT Conditions

[0084] a) Preparation of SCAT

[0085] 1 g of pll that had not been separately preactivated and 3.4 g ofsilica gel 60 (230-400 mesh, Merck) were mixed, suspended in 30 ml ofanhydrous THF, and stirred slowly for 48 h with exclusion of light. Thesuspension was filtered and the residue was washed twice with 10 ml ofanhydrous THF each time. The material (SCAT) was dried in vacuo overP₂O₅.

[0086] b) Epoxidation Under SCAT Conditions with PTC

[0087] 50 mg of trans-chalcone, 35 mg of urea/hydrogen peroxide complex(UHP, 0.36 mmol, 1.5 equivalents), 8.5 mg of [(C₄H₉)₄N⁺]Br⁻, and 100 mgof SCAT (11 mol %) were mixed and, after suspending with 1.5 ml ofanhydrous THF, 55 μl of DBU (1.5 equivalents) were added. The reactionmixture was allowed to react with stirring at room temperature. After areaction time of 30 min, the reaction mixture was filtered andconcentrated under reduced pressure.

Comparative Example CE 4 SCAT Conditions without PTC

[0088] a) Preparation of SCAT

[0089] 1 g of non-separately preactivated p1l and 3.4 g of silica gel 60(230-400 mesh, Merck) were mixed, suspended in 30 ml of anhydrous THF,and stirred slowly for 48 h with exclusion of light. The suspension wasfiltered and the residue was washed twice with 10 ml of anhydrous THFeach time. The material (SCAT) was dried in vacuo over P₂O₅.

[0090] b) Epoxidation under SCAT Conditions Without PTC

[0091] 50 mg of trans-chalcone, 35 mg of urea/hydrogen peroxide complex(UHP, 0.36 mmol, 1.5 equivalents), and 100 mg of SCAT (11 mol %) weremixed and, after suspending with 1.5 ml of anhydrous THF, 55 μl of DBU(1.5 equivalents) were added. The reaction mixture was allowed to reactwith stirring at room temperature. After a reaction time of 30 min, thereaction mixture was filtered and concentrated under reduced pressure.

[0092] The results of Examples 1 and 3 and of Comparative Examples CE 2and 4 are compiled in the table below. TABLE Reac- tion Exam- timeConversion ee ple Conditions PTC [min] [%] [%] 1 according to the[(C₄H₉)₄N⁺]Br⁻ 30 >99 78 invention CE 2 2-phase; not — 30 >99 53according to the invention 3 according to the [(C₄H₉)₄N⁺]Br⁻ 30 >99 92invention CE 4 2-phase, SCAT; — 30 >99 86 not according to the invention

What is claimed is:
 1. A process comprising epoxidizing α,β-unsaturatedenones or α,β-unsaturated sulfones in the presence of (1) an organicsolvent, (2) a base, (3) an oxidant, (4) a diastereomer- andenantiomer-enriched homo-polyamino acid as catalyst that has not beenseparately preactivated, and (5) a phase-transfer catalyst, but withoutaddition of water.
 2. A process according to claim 1 wherein thephase-transfer catalyst is a quaternary ammonium salt, quaternaryphosphonium salt, onium compound, or pyridinium salt.
 3. A processaccording to claim 2 wherein the phase-transfer catalyst is a quaternaryammonium or phosphonium salt of the formula (I) (R¹R²R³R⁴A)⁺X⁻  (I) inwhich A is N or P, X⁻ is an inorganic or organic anion, R¹ and R² areidentical or different and are alkyl, aryl, aralkyl, cycloalkyl, orheteroaryl radicals that are optionally substituted by one or moreidentical or different halogen radicals, and R³ and R⁴ are identical ordifferent and are alkyl, aryl, aralkyl, cycloalkyl, or heteroarylradicals or R³ and R⁴ together form a C₄-C₆-cycloalkyl ring with A.
 4. Aprocess according to claim 3 wherein X⁻ is F⁻, Cl⁻, Br⁻, I⁻, OH⁻, NO₃ ⁻,HSO₄ ⁻, SO₄ ⁻, CH₃COO⁻, CF₃COO⁻, C₂H₅COO⁻, C₃H₇COO⁻, CF₃SO₃ ⁻or C₄F₉SO₃⁻.
 5. A process according to claim 3 wherein, for the phase-transfercatalysts of the formula (I), R¹, R², R³, and R⁴ are identical ordifferent and are C₁-C₁₈-alkyl, C₆-C₁₈-aryl, C₇-C₁₉-aralkyl,C₅-C₇-cycloalkyl, or C₃-C₁₈-heteroaryl.
 6. A process according to claim3 wherein the phase-transfer catalyst is ((C₄H₉)₄N)⁺Hal⁻,((C₄H₉)₄P)⁺Hal⁻, ((C₄H₉)₄N)⁺HSO₄ ⁻, ((C₈H₁₇)₄N)⁺Br⁻,[(CH₃)(C₈H₁₇)₃N]⁺Cl⁻, or [(CH₃)(C₄H₉)₃N]⁺Cl⁻.
 7. A process according toclaim 1 wherein the phase-transfer catalyst is employed in an amount inthe range 0.1 to 20 mol %, based on the α,β-unsaturated enone orα,β-unsaturated sulfone employed.
 8. A process according to claim 1wherein the α,β-unsaturated enones or α,β-unsaturated sulfones have theformula (II)

in which X is (C═O) or (SO₂), and R⁵ and R⁶ are identical or differentand are (C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₇-C₁₉)-aralkyl,(C₁-C₁₈)-heteroaryl, or (C₂-C₁₉)-heteroaralkyl, each of which radicalsis optionally substituted once or more than once by identical ordifferent radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸, SO₀₋₃R⁷, OR⁷,CO₂R⁷, CONHR⁷, or COR⁷, and where optionally one or more CH₂ groups inR⁵ and R⁶ are replaced by O, SO₀₋₂, NR⁷, or PO₀₋₂R⁷, where R⁷ and R⁸ areidentical or different and are H, (C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl,(C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl,(C₁-C₁₈)-heteroaryl, (C₁-C₈)-alkyl-(C₆-C₈)-aryl,(C₁-C₈)-alkyl-(C₁-C₁₈)-heteroaryl, or (C₁-C₈)-alkyl-(C₃-C₈)-cycloalkyl,each of which radicals R⁷ and R⁸ is optionally substituted once or morethan once by identical or different halogen radicals.
 9. A processaccording to claim 1 wherein the α,β-unsaturated enones orα,β-unsaturated sulfones have the formula (II)

in which X is (C═O) or (SO₂), R⁵ and R⁶ are identical or different andare (C₁-C₁₂)-alkyl, (C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl,(C₅-C₈)-cycloalkyl, (C₆-C₁₂)-aryl, or (C₁-C₁₂)-heteroaryl, each of whichradicals is optionally substituted once or more than once by identicalor different radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸, or OR⁷, and R⁷and R⁸ are identical or different and are H, (C₁-C₁₈)-alkyl,(C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl,(C₁-Cl₈)-heteroaryl, (C₁-C₈)-alkyl-(C₆-C₈)-aryl,(C₁-C₈)-alkyl-(C₁-C₁₈)-heteroaryl, or (C₁-C₈)-alkyl-(C₃-C₈)-cycloalkyl,each of which radicals R⁷ and R⁸ is optionally substituted once or morethan once by identical or different halogen radicals.
 10. A processaccording to claim 1 wherein the α,β-unsaturated enones orα,β-unsaturated sulfones are compounds of the formula (II)

in which X is (C═O) or (SO₂), R⁵ and R⁶ are identical or different andare (C₁-C₁₂)-alkyl, (C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl,(C₅-C₈)-cycloalkyl, (C₆-C₁₂)-aryl, or (C₁-C₁₂)-heteroaryl, each of whichradicals is optionally substituted once or more than once by identicalor different radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸, or OR⁷, and ⁷and R⁸ are identical or different and are H, (C₁-C₁₈)-alkyl,(C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl,(C₁-C₁₈)-heteroaryl, (C₁-C₈)-alkyl-(C₆-C₈)-aryl,(C₁-C₈)-alkyl-(C₁-C₁₈)-heteroaryl, or (C₁-C₈)-alkyl-(C₃-C₈)-cycloalkyl,each of which radicals R⁷ and R⁸ is optionally substituted once or morethan once by identical or different halogen radicals, with the provisothat at least one of the radicals R⁵ or R⁶ is a (C₂-C₁₂)-alkenyl,(C₂-C₁₂)-alkynyl, (C₆-C₁₂)-aryl-, or (C₁-C₁₂)-heteroaryl radical.
 11. Aprocess according to claim 1 wherein the α,β-unsaturated enones orα,β-unsaturated sulfones are compounds of the formula (III)

where n and m are identical or different and are the numbers 0, 1, 2 or3, R⁹ and R¹⁰ are identical or different and are NR⁷R⁸, NO₂, OR⁷,(C₁-C₁₂)-alkyl, (C₂-C₁₂)-alkenyl, (C₂-C₁₂)-alkynyl, (C₅-C₈)-cycloalkyl,(C₆-C₁₂)-aryl, or (C₁-C₁₂)-heteroaryl, each of which radicals R⁹ and R¹⁰is optionally substituted once or more than once by identical ordifferent halogen radicals, and R⁷ and R⁸ are identical or different andare H, (C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₁-C₁₈)-heteroaryl,(C₁-C₈)-alkyl-(C₆-C₈)-aryl, (C₁-C₈)-alkyl-(C₁-C₁₈)-heteroaryl, or(C₁-C₈)-alkyl-(C₃-C₈)-cycloalkyl, each of which radicals R⁷ and R⁸ isoptionally substituted once or more than once by identical or differenthalogen radicals.
 12. A process according to claim 1 wherein thediastereomer- and enantiomer-enriched homo-polyamino acids are selectedfrom the group consisting of polyneopentylglycine, polyleucine,polyisoleucine, polyvaline, polyalanine, and polyphenylalanine.
 13. Aprocess according to claim 1 wherein the polyamino acid has a chainlength in the range from 5 to 100 amino acid repeating units.
 14. Aprocess according to claim 1 wherein the homo-polyamino acid is employedin the range 0.0001 to 40 mol %, based on the α,β-unsaturated enone orα,β-unsaturated sulfone employed.
 15. A process according to claim 1wherein the homo-polyamino acids are applied by adsorption to aninsoluble support material.
 16. A process according to claim 15 whereinthe insoluble support material is based on silica, zeolite, or activatedcarbon or sugar derivatives.
 17. A process according to claim 1 whereinthe oxidant is a hydrogen peroxide complex with an inorganic carbonate,tertiary amine, amino oxide, amide, phosphane, or phosphane.
 18. Aprocess according to claim 1 wherein 1 to 40 equivalents of the oxidantis employed.
 19. A process according to claim 1 wherein the base is anorganic or inorganic base.
 20. A process according to claim 1 whereinthe base is an organic, non-nucleophilic base.
 21. A process accordingto claim 1 wherein the base is 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, or (1,4-diazabicyclo[2.2.2]octane. 22.A process according to claim 1 wherein 0.1 to 10 equivalents of the baseis employed.
 23. A process according to claim 1 wherein organic solventis an ether, ester, amide, or sulfoxide.
 24. A process according toclaim 1 wherein the temperature used in the epoxidation is in the rangefrom −10 to +50° C.